The goal of this work is to demonstrate that the normal process of epidermal desquamation can be harnessed to eliminate systemic toxins from the body. This proposal focuses on iron as a model toxin. Iron is essential for life, but too much iron causes the disease hemochromatosis. Normally, 20% of absorbed iron is eliminated through epidermal desquamation. The central hypothesis is that if epidermis can be made to act as a sink for internal iron, then epidermal shedding might reduce the body burden of iron. AIM I. tests the feasibility of this approach by experiments designed to reduce the systemic iron burden in the Hfe null mouse model of heriditary hemochromatosis. A. We will cause epidermis to act as a sink or sponge for iron and then measure the effect on iron stores in internal organs: 1. by breeding experiments leading to over-expression of the transferrin receptor in epidermis; 2. by topical application of iron ionophores or iron chelators; B. We will accelerate cutaneous iron loss through increased epidermal turnover and desquamation: 1. by breeding experiments leading to over-expression of the viral E7 protein in epidermis; 2. by systemic administration of a synthetic retinoid; AIM II investigates the physiology and pathophysiology of iron in mouse keratinocyte cultures and in mouse epidermis. The goal is to identify better ways of causing epidermis to act as a sink for iron and to test whether elevated iron in epidermis is toxic. A. We will identify additional ways to increase iron accumulation in epidermis 1. by characterizing expression and function of iron export protein ferroportin in epidermis; 2. by using hepcidin to regulate expression of ferroportin; B. We will evaluate whether epidermal iron increases the risk for phototoxicity, DNA mutagenesis or skin cancer, using our transgenic mice in which iron accumulation is restricted to epidermis. Relevance: This proposal represents a novel approach to the elimination of systemic toxins by causing them to be shed from the skin surface. By focusing on iron, it also will provide basic new information to fill existing gaps in knowledge about the physiology and pathophysiology of iron in the epidermis. Since iron is increasingly suspected of having a role in inflammatory and neoplastic diseases of skin, this new information should assist in devising preventative and treatment measures for those types of diseases.